Immune disorders are characterized by the inappropriate activation of the body's immune defenses. Rather than targeting infectious invaders, the immune response targets and damages the body's own tissues or transplanted tissues. The tissue targeted by the immune system varies with the disorder. For example, in multiple sclerosis, the immune response is directed against the neuronal tissue, while in Crohn's disease the digestive tract is targeted.
Immune disorders affect millions of individuals and include conditions such as asthma, allergic intraocular inflammatory diseases, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anaemia, inflammatory dermatoses, inflammatory bowel or gastrointestinal disorders (e.g., Crohn's disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritis/inflammation, psoriasis, rheumatoid arthritis, cirrhosis, and systemic lupus erythematosus.
A major cellular pathway in the pathogenesis of autoimmunity is the TLR/IRAK1/IRF/IFN pathway. For example, levels of IFNα (type I interferon) are elevated in patients with autoimmune diseases, including systemic lupus erythematosus (SLE), and are central to disease pathogenesis, correlating with autoantibodies and disease development. Recent genetic studies in SLE patients and lupus-prone mice have identified variants in the genes critical for the TLR/IRAK1/IRF/IFN pathways, including TLR7, IRAK1 and IRF5. In addition, several TLR inhibitors are in development for treatment of SLE. Notably, IRAK1 genetic variants have recently been identified in human SLE. IRAK1, a well-established pivotal player in TLRs and inflammation, is located on the X chromosome, which may help account for the fact that SLE is more common in women. Importantly, studies using mouse models, where the IRAK1 gene is removed, have demonstrated a key role for this kinase in the TLR7/9/IRF pathway that produces large quantities of IFNα in response to viral infection. Immune cells responsible for producing large quantities of IFNα are called pDCs. IRAK1 gene deletion prevents TLR dependent activation of IRF5/7 in pDCs and IFNα production. Significantly, autoantibody complexes obtained from SLE patients contain DNA and RNA and are taken up by pDCs to activate TLR7 and TLR9 leading to secretion of cytokines and IFNα. Moreover, TLR activation is known to inhibit activity of glucocorticoids, a frontline drug used to treat SLE. Although IRAK1 activity is regulated by phosphorylation upon TLR activation, little is known about whether it is subject to further control after phosphorylation and whether such regulation has any role in SLE.
The prevalence of asthma is increasing in the developed world, but the underlying mechanisms are not fully understood, and therapeutic modalities remain limited. Asthma is a chronic inflammatory disease of the airways that is induced by overexpression of multiple proinflammatory genes regulated by various signal pathways in response to exposure to any of numerous allergens, including Toll-like receptor/interleukin-1 receptor (TLR/IL-1R) signaling activated by house dust mite (HDM) allergens and IL-33, respectively. A major regulatory mechanism in these signal pathways and gene activation is Pro-directed phosphorylation (pS/T-P), but until recently little was known about whether and how they are regulated following phosphorylation.
Current treatment regimens for immune disorders typically rely on immunosuppressive agents. The effectiveness of these agents can vary and their use is often accompanied by adverse side effects. Thus, improved therapeutic agents and methods for the treatment of autoimmune disorders are needed.